Mitigation of radiation injuries via suppression of the renin-angiotensin system: emphasis on radiation nephropathy.

Radiation nephropathy and other normal tissue radiation injuries can be successfully mitigated, and also treated, by antagonists of the renin-angiotensin system (RAS). This implies a mechanistic role for that system in radiation nephropathy, yet no evidence exists to date of activation of the RAS by irradiation. RAS antagonists, including angiotensin converting enzyme inhibitors and angiotensin receptor blockers, are the standard of care in the treatment of subjects with other chronic progressive kidney diseases, in which they exert benefit by reducing both glomerular and tubulo-interstitial injury. These drugs are likely to act in a similar way to mitigate radiation nephropathy.

Chronic kidney disease as a global public health problem: approaches and initiatives - a position statement from Kidney Disease Improving Global Outcomes.

Chronic kidney disease (CKD) is increasingly recognized as a global public health problem. There is now convincing evidence that CKD can be detected using simple laboratory tests, and that treatment can prevent or delay complications of decreased kidney function, slow the progression of kidney disease, and reduce the risk of cardiovascular disease (CVD). Translating these advances to simple and applicable public health measures must be adopted as a goal worldwide. Understanding the relationship between CKD and other chronic diseases is important to developing a public health policy to improve outcomes. The 2004 Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference on 'Definition and Classification of Chronic Kidney Disease' represented an important endorsement of the Kidney Disease Outcome Quality Initiative definition and classification of CKD by the international community. The 2006 KDIGO Controversies Conference on CKD was convened to consider six major topics: (1) CKD classification, (2) CKD screening and surveillance, (3) public policy for CKD, (4) CVD and CVD risk factors as risk factors for development and progression of CKD, (5) association of CKD with chronic infections, and (6) association of CKD with cancer. This report contains the recommendations from the meeting. It has been reviewed by the conference participants and approved as position statement by the KDIGO Board of Directors. KDIGO will work in collaboration with international and national public health organizations to facilitate implementation of these recommendations.

Treatment of radiation nephropathy with ACE inhibitors and AII type-1 and type-2 receptor antagonists.

Radiation nephropathy has emerged as a significant complication of bone marrow transplantation and radionuclide radiotherapy, and is a potential sequela of radiological terrorism and radiation accidents. In the early 1990's, it was demonstrated that experimental radiation nephropathy could be treated with a thiol-containing ACE inhibitor, captopril. Further studies have shown that enalapril (a non-thiol ACE inhibitor) is also effective in the treatment of experimental radiation nephropathy, as are both AII type-1 (AT(1)) and type-2 (AT(2)) receptor antagonists. ACE inhibitors and AII receptor antagonists are also effective in the mitigation (prevention) of radiation nephropathy. Other types of antihypertensive drugs are ineffective in mitigation, but brief use of a high-salt diet in the immediate post-irradiation period significantly decreases renal injury. There are differences between mitigation and treatment of radiation nephropathy that imply that different mechanisms are operating. First, a high-salt diet is effective in the mitigation of radiation nephropathy, but deleterious on the treatment of established disease. Second, AT(1) blockade is more effective than ACE inhibition for mitigation of radiation nephropathy, but equally effective for treatment. Third, the efficacy of AT(1) blockade and ACE inhibition is highly dependent on drug dose in mitigation of radiation nephropathy, but not so in treatment. Finally, while AT(2) blockade augments the benefit of AT(1) blockade in mitigation of radiation nephropathy, it does not do so in treatment. We hypothesize that while mitigation of radiation nephropathy works by suppression of the renin-angiotensin system, treatment of established radiation nephropathy requires blood pressure control in addition to (or possibly instead of) suppression of the renin-angiotensin system.

Hypertension and the kidney.

The kidney could be the cause of essential hypertension which can also cause renal disease. High blood pressure is also very common in chronic kidney disease, and is moreover a well-known risk factor for a faster progression of kidney failure. Hypertension and kidneys are thus closely linked. Hypertension must be aggressively treated in patients suffering from chronic kidney disease, with a blood pressure goal of less than 130/80 mmHg, even lower than 125/75 mmHg when proteinuria is over 1g/day, using optimal and effective antihypertensive drugs. Among them, the blockers of the renin-angiotensin axis offer nephroprotective but also cardioprotective properties beyond their effect on blood pressure.

T-regulatory cells are relatively deficient in squamous carcinomas undergoing regression in mice immunized with a squamous carcinoma vaccine enriched for immunotherapeutic cells.

In a prior report (Int J Cancer 2006; 119: 339-348), we described a new vaccination strategy for squamous cell carcinoma (SCC). The vaccine was prepared by transfer of unfractionated DNA-fragments (25 kb) from KLN205 cells, a squamous carcinoma cell line (DBA/2 origin; H-2(d)) into LM cells, a highly immunogenic mouse fibroblast cell line (C3H/He origin; (H-2(k))). As only a small proportion of the transfected cell population was expected to have incorporated DNA segments that included genes specifying antigens associated with the squamous carcinoma cells, we devised a novel strategy to enrich the vaccine for immunotherapeutic cells. Enhanced immunity to squamous carcinoma was induced in tumor-bearing mice treated solely by immunization with the enriched vaccine, which translated into prolonged survival without toxicity. Here, we describe the characteristics of the cell populations infiltrating established squamous carcinomas undergoing regression in mice immunized with vaccines enriched for immunotherapeutic cells. The results indicated that CD8+ T cells were predominant and that T-regulatory cells (FoxP3+, CD4/CD25+, CD4/CD62L(high), CD4/CTLA-4e) were relatively deficient in the regressing tumors. Inflammatory infiltrates were not detected in various organs and tissues of mice immunized with the DNA-based vaccine.

New strategy for the identification of squamous carcinoma antigens that induce therapeutic immune responses in tumor-bearing mice.

This study describes a new strategy for the identification of squamous carcinoma antigens tumor-associated antigens (TAA). The antigens were discovered by comparing microarrays of squamous carcinoma vaccines highly enriched for immunotherapeutic cells with non-enriched vaccines. The vaccines were prepared by transferring sheared genomic DNA fragments (25 kb) from KLN205 cells, a squamous carcinoma cell line (DBA/2 mouse origin (H-2(d)) into LM fibroblasts (C3H/He origin, H-2(k)). The transferred tumor DNA segments integrate spontaneously into the genome of the recipient cells, replicate as the cells divide and are expressed. As only a small proportion of the transfected cell population was expected to have incorporated DNA segments that included genes specifying TAA (the vast majority specify normal cellular constituents), a novel strategy was employed to enrich the vaccine for TAA-positive cells. Microarrays were used to compare genes expressed by enriched and non-enriched vaccines. Seventy-five genes were overexpressed in cells from the enriched vaccine. One, the gene for Cytochrome P450 (family 2, subfamily e, polypeptide 1) (Cyp2e1), was overexpressed in the enriched but not the non-enriched vaccine. A vaccine for squamous carcinoma was prepared by transfer of a 357 bp fragment of the gene for Cyp2e1 into the fibroblast cell line. Robust immunity, sufficient to result in indefinite survival, was induced in tumor-bearing mice immunized with cells transfected with this gene fragment.

[The physiopathology of dialysis-associated hypertension]. / La physiopathologie de l'hypertension artérielle en dialyse chronique.

Hypertension in subjects on long term dialysis is frequent. Its origins are found in extracellular volume overload, which is complicated by increased peripheral arterial resistance. The latter is affected by many systems, including that of renin-angiotensin, endothelin, nitric oxide, the sympathetic nervous system, and others. The interaction between these factors may explain why the control of hypertension in dialysis patients requires ongoing attention to the many aspects of good dialysis.

Salt, the kidneys, and arterial hypertension.

The kidneys play a major role in the regulation of the salt balance and thereby regulate blood pressure. Salt sensitivity is acquired or genetically-induced and is noted in about 50% of patients with essential hypertension. This property leads to a high cardiovascular risk. In this situation, the benefit of salt restriction is significant, and this dietary change should be associated with a high potassium intake. In patients treated by antihypertensive drugs, salt restriction improves the blood pressure control, which can permit a reduction of the number of drugs required to achieve a normal blood pressure. The recommended maximal salt intake should not exceed 6 grams/day (NaCl). Because most dietary salt comes from processed foods, the help of the food industry is crucial for a long-term compliance with a reduced salt intake, which could yield an additional important benefit in the reduction of cardiovascular risk.

ACE inhibitors and AII receptor antagonists in the treatment and prevention of bone marrow transplant nephropathy.

Radiation nephropathy has emerged as a major complication of bone marrow transplantation (BMT) when total body irradiation (TBI) is used as part of the regimen. Classically, radiation nephropathy has been assumed to be inevitable, progressive, and untreatable. However, in the early 1990's, it was demonstrated that experimental radiation nephropathy could be treated with a thiol-containing ACE inhibitor, captopril. Further studies showed that enalapril (a non-thiol ACE inhibitor) was also effective in the treatment of experimental radiation nephropathy, as was an AII receptor antagonist. Studies also showed that ACE inhibitors and AII receptor antagonists were effective in the prophylaxis of radiation nephropathy. Interestingly, other types of antihypertensive drugs were ineffective in prophylaxis, but brief use of a high-salt diet in the immediate post-irradiation period decreased renal injury. A placebo-controlled trial of captopril to prevent BMT nephropathy in adults is now underway. Since excess activity of the renin-angiotensin system (RAS) causes hypertension, and hypertension is a major feature of radiation nephropathy; an explanation for the efficacy of RAS antagonism in the prophylaxis of radiation nephropathy would be that radiation leads to RAS activation. However, current studies favor an alternative explanation, namely that the normal activity of the RAS is deleterious in the presence of radiation injury. On-going studies suggest that efficacy of RAS antagonists may involve interactions with a radiation-induced decrease in renal nitric oxide activity or with radiation-induced tubular cell proliferation. We hypothesize that while prevention (prophylaxis) of radiation nephropathy with ACE inhibitors, AII receptor antagonists, or a high-salt diet work by suppression of the RAS, the efficacy of ACE inhibitors and AII receptor antagonists in treatment of established radiation nephropathy depends on blood pressure control.

Dietary sodium modification and experimental radiation nephropathy.

PURPOSE: To determine whether suppression of the renin-angiotensin system (RAS) with high dietary sodium (salt) has the same beneficial effect on radiation nephropathy as suppression of the RAS with angiotensin-converting-enzyme (ACE) inhibitors or angiotensin II (AII) receptor antagonists. MATERIALS AND METHODS: Normal and irradiated rats were placed on high- or low-salt diets and assessed for effects on blood pressure, on AII levels and on the development of radiation nephropathy. RESULTS: In unirradiated animals, a high-salt diet suppressed AII and caused hypertension, while a low-salt diet produced no detectable effects. Use of a high-salt diet 3-9 weeks after irradiation exacerbated radiation-induced hypertension but attenuated the development of radiation nephropathy. Continuous use of a high-salt diet slowed the progression of radiation nephropathy, but eventually exacerbated radiation-induced hypertension and accelerated renal failure. Use of a high-salt diet in animals with established radiation nephropathy was deleterious. A low-salt diet had no effect on the development of radiation nephropathy. CONCLUSIONS: These studies provide further support for the hypothesis that the beneficial effect of AII receptor antagonists, ACE inhibitors and high dietary sodium in the prophylaxis of radiation nephropathy is due to their suppression of the RAS, not to their anti-hypertensive effects.

An optimum anti-melanoma response in mice immunized with fibroblasts transfected with DNA from mouse melanoma cells requires the expression of both syngeneic and allogeneic MHC-determinants.

Most neoplasms do not induce antitumor immune responses that can control tumor growth. Tumor associated antigens (TAAs) are insufficiently immunogenic. A vaccine that augments the immunogenic properties of TAAs could be of importance in the treatment of cancer patients. In an animal model, we prepared a vaccine by transfection of highly antigenic allogeneic mouse fibroblasts (LM; H-2(k)) with DNA from B16 mouse melanoma cells. We then tested the transfected cells' immunogenic properties in C57BL/6 mice, syngeneic with the melanoma (H-2(b)). We hypothesized that the immunogenic properties of 'weak' TAAs formed by the neoplasm would be enhanced if they were expressed by highly antigenic cells. The results indicated that mice with melanoma treated by immunization with the DNA-transfected fibroblasts survived significantly longer than mice in various control groups. To investigate the contribution of MHC determinants expressed by the transfected cells to their immunogenic properties, we compared the antimelanoma responses in mice immunized with transfected cells that expressed allogeneic or syngeneic class I determinants. The results indicated that the immunogenic properties of the DNA-transfected cells were enhanced if the cells expressed allogeneic MHC determinants. The antimelanoma responses of greatest magnitude, however, mediated predominantly by CD8(+) T cells, were in mice immunized with transfected fibroblasts that expressed both syngeneic and allogeneic class I determinants.

The glomerulo-tubular junction: a target in renal diseases.

Both global and segmental glomerulopathies may damage specific areas of the renal glomerulus. Diseases associated with glomerular hyperperfusion cause lesions at the vascular pole, while diseases associated with proteinuria often damage the tubular pole. Atubular glomeruli are now known to be plentiful in a variety of common renal diseases. These glomeruli are disconnected from their tubule at the tubular pole and therefore cannot participate in the production of urine. It is widely believed that the disconnection is a result of external compression by periglomerular fibrosis. However, the variable anatomy and cell populations within both the glomerulus and the beginning of the proximal tubule at the glomerulo-tubular junction may also have important roles to play in the response to damage at this sensitive site of the nephron.

Prevention of radiation-induced nephropathy and fibrosis in a model of bone marrow transplant by an angiotensin II receptor blocker.

Nephropathy, interstitial pneumopathy, and renal and lung fibrosis are major complications of bone marrow transplantation (BMT). This study evaluated the antifibrotic property of an angiotensin II (A2) type-1 receptor blocker (L-159,809) and compared it with those of Captopril and Enalapril, two angiotensin-converting enzyme (ACE) inhibitors, in a rat model of BMT. Male WAG/Rij/MCW rats received a preparative regimen of 60 mg/kg body wt of cytoxan (i.p., Days 9 and 8) and 18.5 Gy of total body irradiation (TBI) in six twice daily fractions (Days 2, 1, and 0) followed immediately (Day 0) by BMT. Modifiers were given in drinking water from Day 10 until autopsy, 8 weeks after BMT. Rats treated with TBI plus cytoxan alone developed severe nephropathy. Trichrome staining showed marked collagen deposition in glomeruli, renal interstitium, and renal arteries and arterioles (especially in their adventitia). Collagen deposition and renal damage were markedly reduced by the three modifiers. Of the three, L-158,809-treated rats had slightly thinner vessels and slightly less collagen than nonirradiated normal controls. The study shows the effectiveness of these drugs in the protection of the renal parenchyma from the development of radiation-induced fibrosis. It also indicates a role for angiotensin II in the modulation of collagen synthesis.

Parathyroidectomy in chronic renal failure: has medical care reduced the need for surgery?

Subtotal or total parathyroidectomy is sometimes required for the management of severe secondary or tertiary hyperparathyroidism. Advances in medical and dialysis care may have a beneficial effect on hyperphosphatemia and vitamin D status, which could, in turn, reduce the need for parathyroidectomy. We used the United States Renal Data System to test this hypothesis. We found that the percentage of prevalent end-stage renal disease patients undergoing subtotal or total parathyroidectomy has declined significantly from 1988 to 1998. It is likely that improved medical and dialysis care has enabled this result.

Polyoma virus infection after renal transplantation. Use of immunostaining as a guide to diagnosis.

BACKGROUND: Polyoma virus infection is characterized by lymphocytic interstitial infiltrate in the kidney, and it mimics acute rejection. The purpose of this study is to estimate renal allograft outcome with this infection and characterize the lymphocytic infiltrates in polyoma virus-infected renal allografts. METHODS: Patients who had polyoma virus inclusions in renal allograft biopsies were identified. Other viral inclusions were excluded by immunohistochemistry. The lymphocytic infiltrates of six cases of polyoma virus infection were compared with six cases of definite acute rejection by immunostaining for T and B cells. RESULTS: There were 10 cases of polyoma virus infections in renal transplant recipients. Immunosuppressants consisted of mycophenolate mofetil with tacrolimus in eight cases and mycophenolate mofetil with cyclosporine in two. The median time of diagnosis of polyoma virus infection after transplantation was 9.5 months, and the time to graft failure after the diagnosis was 4 months. Reduced allograft survival was seen in patients who had polyoma virus infection. Immunostaining for T and B cells revealed marked increase in the B cells (CD20) in renal allografts with polyoma virus infection of 21% (range, 5-40%) compared with 6% (range, 0-10%) in those with acute rejection (P=0.039). Reduced cytotoxic T cells (TIA-1: median, 7%; range, 2-15%) were seen in polyoma virus-infected allografts compared with 24% (range, 15-30%) in those patients who had acute rejection (P=0.0159). CONCLUSION: Irreversible graft failure is more prevalent with polyoma virus infection. Enhanced immunosuppressants with mycophenolate mofetil with tacrolimus may play a role in the development of this infection. An increase in CD20 and a decrease in cytotoxic T cells in allografts is characteristic of polyoma virus infection.

Subtotal parathyroidectomy in renal failure: still needed after all these years.

There are scant data on the frequency of parathyroidectomy (PTX) for end-stage renal disease (ESRD). Medical therapy for ESRD and secondary hyperparathyroidism has evolved to include better dialytic urea removal and the use of calcitriol. The aim of this study was to determine whether medical therapy has changed the frequency or indications for PTX in the management of renal failure. Hospital and clinic records were analyzed to gather information on all patients undergoing PTX for secondary hyperparathyroidism (2HPT) (n = 48) and tertiary hyperparathyroidism (3HPT) (n = 26) from 1986 through 1998 at our institution. Prospective computer databases were queried for information concerning both chronic dialysis and renal transplant patients at our center. The patients were divided based on date of operation before or after 1991, a divider that separated the patients into groups before or after the widespread adoption of intravenous calcitriol treatment during hemodialysis at our institution. Over the 12 year period, the proportion of our chronic dialysis patients undergoing PTX did not change significantly, ranging from 0% to 2.5% per year. Comparing all patients undergoing PTX for 2HPT during 1986-1991 versus 1992-1998, there was no significant difference in time on dialysis [7.0 +/- 4.2 (n = 11) vs. 7.5 +/- 4.6 (n = 36) years, mean +/- SD]. The later group had higher intact parathyroid hormone (iPTH) levels [765 +/- 415 (n = 6) vs. 1377 +/- 636 (n = 28) pg/ml; p = 0.03], lower serum calcium [11.2 +/- 1.0 (n = 12) vs. 9.9 +/- 1.5 (n = 34) mg/dl; p = 0.006], and higher serum phosphate [5.7 +/- 1.6 (n = 12) vs. 7.2 +/- 2.3 (n = 31) mg/dl; p = 0.042]. Among the population of patients with transplants undergoing PTX for 3HPT, the average percent per year undergoing PTX ranged from 0% to 4.2% and did not change during the study period. Comparing the 1986-1991 group to the 1992-1998 group, the time from transplantation to PTX did not change during the study period (3.3 +/- 2.3 vs. 2.9 +/- 3.0 years; p = 0.391), and there were no significant differences between preoperative calcium levels or iPTH levels. Despite advances in dialysis technique and pharmacologic therapy, there has been no change in the proportion of dialysis patients requiring PTX for 2HPT or 3HPT. There was also no change in the time on dialysis for patients with 2HPT or the time from transplant to PTX for patients with 3HPT. Analysis of preoperative biochemical markers as evidence of disease severity suggests there was no change in indications for PTX during our study. From this information we conclude that parathyroid pathophysiology is incompletely understood and medical therapy is not optimal, resulting in a continuing need for PTX in some patients.

Loss of renal function following bone marrow transplantation: an analysis of angiotensin converting enzyme D/I polymorphism and other clinical risk factors.

Chronic renal failure is an acknowledged late complication of BMT. It is related to the intensive chemotherapy, radiation and supporting medications. Polymorphism in the angiotensin converting enzyme (ACE) gene is associated with progression of nephropathy caused by diabetes and IgA nephropathy. We sought to determine whether ACE genotype and other clinical factors were associated with loss of renal function after BMT. We determined the genotype of 106 adult allogeneic BMT recipients, who received a similar preparative regimen, survived 1 year, and had assessment of renal function up to 3 years after BMT. We found that the distribution of genotypes was similar to the general population; 29%, 51%, and 20% for the DD, DI, and II genotypes, respectively. There was no statistical difference in patient survival between the three groups. Among all patients, the average creatinine clearance declined from 124 (95% CI 117, 131) to 89 (95% CI 78, 100) ml/min over the 36 months after BMT. Decline in renal function over time was less for patients with the DD compared to the II genotype (P = 0.040). Renal function in patients with the DD genotype was also better than those with the DI genotype, but this was of borderline statistical significance (P = 0.055). Renal shielding reduced decline in renal function compared to no shielding (P = 0.026). We conclude that the ACE genotype does not seem to influence survival, but the DD genotype may be protective against renal injury after BMT. Furthermore, we confirm that renal shielding during TBI reduces the renal injury after BMT.